Zirconium oxide and zirconium nitride coated vascular grafts

ABSTRACT

Vascular grafts fabricated from a substrate of a low modulus metal coated with blue to black zirconium oxide or zirconium nitride. The coating provides enhanced thrombogenicity, biocompatibility, blood compatibility, corrosion-resistance, friction and microfretting resistance, durability, and electrical insulation, where applicable. The coatings may be applied to low modulus metallic substrates by physical or chemical vapor deposition as well as other ion-beam assisted methods. Preferably, however, for optimizing attachment strength, the vascular grafts are fabricated from zirconium or zirconium-containing alloys and the coatings are formed by oxidizing or nitriding through an in situ method that develops a coating from and on the metal surface of the vascular graft, without need for depositing a coating on the metal surface.

RELATED APPLICATIONS

This is a division of application Ser. No. 08/112,587, filed on Aug. 26,1993, issued as U.S. Pat. No. 5,496,359, which is a continuation-in-partof U.S. Ser. No. 07/919,932, filed Jul. 27, 1992, issued as U.S. Pat.No. 5,282,850, which is in turn a continuation-in-part of U.S. Ser. No.07/830,720, filed Feb. 4, 1992, issued as U.S. Pat. No. 5,258,022, whichis a continuation-in-part of Ser. No. 07/557,173, filed Jul. 23, 1990,issued as U.S. Pat. No. 5,152,794, which is in turn acontinuation-in-part of U.S. Ser. No. 07/385,285, filed Jul. 25, 1989,issued as U.S. Pat. No. 5,037,438.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is of vascular grafts of enhanced biocompatibility, bloodcompatibility, and corrosion resistance. More specifically, theinvention grafts are fabricated from relatively low modulus metals, suchas zirconium or a zirconium-containing alloy, and are coated with blueto black zirconium oxide or zirconium nitride to provide enhanced bloodcompatibility, microfretting resistance, electrical insulation, andcorrosion resistance where applicable.

2. Description of the Related Art

With advances in the technology for treating heart diseases, there hasdeveloped an increasing demand for sophisticated cardiovascular implantsand surgical tools for use in cardiovascular surgery.

For example, vascular grafts are used to replace damaged blood vessels.These grafts may be fabricated from biocompatible organic polymers, suchas woven dacron, silicone, polyurethane, and the like. Others are not ofwoven polymers, but are simply smooth cylindrical tube sections (i.e.,allographs or autographs) that replace the section of removed artery orvein. While these grafts are fabricated from biocompatible polymers, itis frequently desirable to have a graft fabricated from a bloodcompatible metal that will retain its shape, not degrade with time, andnot collapse under exerted pressure. While the buildup of a coating ofcertain blood components (such as endothelial cells) that provide asurface compatible with blood is desirable, the metal should desirablybe resistant to a build up of adverse blood components on the graftsurface which might ultimately impede the flow of blood through thegraft.

SUMMARY OF THE INVENTION

The invention provides improved vascular grafts fabricated from a lowmodulus metallic material, such as zirconium and zirconium-containingalloys, covered with a biocompatible, microfretting andcorrosion-resistant, hemocompatible, electrically insulative coating ofblue to black zirconium oxide or yellow to orange zirconium nitride.These coatings are tightly adherent to the underlying metal and are of asufficient thickness to provide the desired electrical insulation, bloodcompatibility, microfretting resistance, and corrosion resistance, asmay be required for the particular vascular graft.

In one embodiment, the invention provides a vascular graft fabricatedfrom a low modulus metallic composition, such as zirconium orzirconium-containing alloys, coated predominately with blue to blackzirconium oxide or zirconium nitride. This coated graft providesenhanced biocompatibility and hemocompatibility, while at the same timeproviding enhanced crush resistance and long life when compared withgrafts fabricated from biocompatible polymeric compositions, such aspolyurethane or dacron. While the graft may be fabricated from tubularsections of low modulus metallic compositions coated with zirconiumoxide or nitride, the graft may also be fabricated from woven wirefabricated from these low modulus metallic compositions. The coating ofblue to black zirconium oxide or zirconium nitride may be applied by anyof a number of processes including physical vapor deposition (PVD) andchemical vapor deposition (CVD) but preferably by a process of in situoxidation or nitridation.

Furthermore, the oxide- or nitride-coated surfaces according to theinvention may be coated with other compositions to further enhancebiocompatibility and performance. For example, phosphatadyl choline,heparin, proteins, or other surface treatment may be applied forreducing platelet adhesion or other adverse cellular or tissue responseto surfaces in contact with blood, or boronated or silver-doped hardenedsurface layers to reduce friction and wear if the graft is subject tomicrofretting or other mechanical wear. In certain instances, it may bedesirable to coat the surfaces according to the invention with amedicament such as an antibiotic, anticoagulant, and the like, as neededfor the particular application.

The thickness of the hard zirconium oxide or nitride coating ispreferably less than about 5 microns (i.e., in the range about 3 toabout 6 microns) for optimal residual compressive stresses and minimaldimensional changes or distortion during oxidation or nitridation.However, the thickness of the coating is frequently not critical, forinstance in the case of vascular grafts where the surface coatingprovides enhanced hemocompatibility and biocompatibility and is notsubject to forces requiring optimal residual compressive stresses. Thus,in this case, the thickness of the coating is limited only by its ownintegrity, i.e., that it is not subject to cracking and spalling,thereby potentially releasing particulates into the body of the patient.Such coatings may range from about 0.1 to about 20 microns or more inthickness.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention can be obtained when thefollowing detailed description of the preferred embodiment is consideredin conjunction with the following drawing, in which:

FIG. 1 is a schematic diagram of a vascular graft of woven low modulusmetallic composition coated with blue to black zirconium oxide orzirconium nitride.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides low modulus metallic vascular grafts coated witha layer of blue to black zirconium oxide or zirconium nitride. Thesecoatings provide a blood compatible, microfretting resistant,electrically insulative, stable, and corrosion resistant ceramiccoating. Furthermore, these ceramic blue to black zirconium oxide orzirconium nitride coatings may be further overlaid with a thin coatingof phosphatadyl choline, heparin, or other surface treatment for furtherreducing platelet adhesion, if the vascular graft will be in contactwith blood. Other medicaments may also be coated onto the ceramicsurfaces of the invention. The ceramic coatings of the invention mayalso be modified by boronation or silver doping to further improvefriction and wear characteristics, if necessary.

The term "low modulus" as used to describe the metallic compositionspreferred in this invention include those metallic compositions thatpreferably have a modulus of elasticity less than about 130 GPa.

The term "blue to black" as used to describe zirconium oxide means thatthe color of the oxide may range from blue to black, depending onzirconium concentration in the oxidized alloy or process conditions thatproduce the coating. Thus, for pure zirconium, the blue to black oxideformed by the preferred in situ process is substantially monocliniczirconium oxide. However, if a zirconium alloy is used, then, for theuseful zirconium alloys, the in situ process will produce a surfacecontaining a mixture of oxides, but still substantially zirconium oxide,to produce the blue to black appearance. If an ion beam depositionassisted or other non-in situ process is used, such as chemical or vapordeposition, then the color of the oxide is not affected by the substratemetal. In this case, the white tetragonal or cubic ZrO₂ is possible aswell. Such coatings are useful as "overlay" coatings on an in situblue-black zirconium oxide or yellow-orange zirconium nitride coating.Since the hardness match between such overlays and the in situ coatingsare closer than between overlay and substrate metal, the coatings aremore firmly attached and have superior integrity. Other hard coatingsare also useful as overlays--such as amorphous diamond-like carboncoatings, wear-resistant coatings formed by silver deposition, andlubricious boronated coatings.

The term "yellow to orange" as applied to zirconium nitride refers tothe range of colors of zirconium nitride and the comments above aboutalloys and consequent mixtures of oxides with zirconium oxide also applyin the nitride context.

FIG. 1 shows a side view of a substantially tubular vascular graft 10,with bore therethrough, made of woven low modulus metallic wires 12coated with blue to black zirconium oxide or zirconium nitride. Whilethe graft shown is made of woven wires of a low modulus metal, such aszirconium or zirconium-containing alloys, the graft can also befabricated from a cylindrical tubing of low modulus metal, coated withblue to black zirconium oxide or zirconium nitride. As explained before,since the coating surface provides the desired thrombogenicity andhemocompatibility, the thickness of the coating is not critical otherthan that it should be dense and well-attached to the substrate.However, it is preferred that the coating thickness range from about 0.1to about 20 microns, more preferably from about 1 to about 10 microns,most preferably about 3-6 microns.

While the oxide and nitride coatings of the invention can be applied byvarious coating methods, in situ coating is preferred. These in situmethods require that the metal composition be zirconium or its alloys sothat the coating can be formed by oxidizing or nitriding the metalitself, not by depositing zirconium oxide or nitride on the metallicsurface by coating deposition methods. Thus, the in situ methods includeoxidation or nitridation in air, oxygen (oxidation), nitrogen(nitridation), and salt baths. These methods are described below.

In order to form continuous and useful zirconium oxide or nitridecoatings over the surface of zirconium or its alloys by an in situmethod, the alloy should contain from about 50 to about 100 wt. %zirconium, preferably about 80 to about 100 wt. %. Common alloyingelements include niobium, tantalum, and titanium, with often times thepresence of hafnium. Yttrium may also be alloyed with the zirconium toenhance the formation of a tougher, yttria-stabilized zirconium oxidecoating during the oxidation of the alloy. During oxidation, theprotective surface layer will contain various amounts of zirconium oxidedepending on the alloy composition. The greater the level of zirconiumoxide, the darker (tending to black) the ceramic oxide appearance.However, this appearance may be blue for alloys with relatively lowerlevels of zirconium or for thinner oxide layers. For ZrO₂ surfaceoxides, the monoclinic structure is stable at room temperature and isblack in appearance. However, higher temperature oxide structures suchas cubic or tetragonal can range from grey to white. While zirconium andzirconium alloys may be custom-formulated by conventional methods knownin the art of metallurgy, a number of suitable alloys are commerciallyavailable. These commercial alloys include among others Zircadyne 705,Zircadyne 702, and Zircalloy, Ti-Zr and Ti-MO-Zr alloys. Ti-Nb-Zr alloysare disclosed in U.S. Pat. No. 5,169,597, entitled "Biocompatible LowModulus Titanium Alloy for Medical Implants" (hereby fully incorporatedby reference) and are the preferred low modulus metals. It should beunderstood that other low modulus metallic compositions not containingzirconium may also be used if the coating is applied by other than insitu methods, e.g., chemical vapor deposition, physical vapordeposition.

To fabricate the coated article by an in situ process, the appropriatesubstrate is first produced and then subjected to process conditionswhich cause the natural (in situ) formation of a tightly adhered,diffusion-bonded coating of essentially zirconium oxide on its surface.The process conditions include, for instance, oxygen-containing gas,steam, or water oxidation or oxidation in a fluidized or salt bath.These processes ideally provide a dense, blue to black, hard,low-friction, wear-resistant zirconium oxide film or coating ofthicknesses typically less than several microns (10⁻⁶ meters) on thesurface of the prosthesis substrate. In some instances, thezirconium-containing oxide coating can be as thin as 0.1-0.2 microns andstill provide useful protection. Typically, below this coating, there isa zone wherein diffused oxygen from the oxidation process increases thehardness and strength of the underlying substrate metal, and optimizescoating durability and attachment strength.

Unlike the prior art titanium oxides of, for example, Steinemann's U.S.Pat. No. 3,643,648, in the preferred in situ oxidation method the oxygensupplied to form the blue, blue to black, zirconium oxide coatings ofthe invention is also a beneficial alloying component which improves theimmediate substrate metal hardness, which in turn improves oxideattachment strength and durability and also improves the base-metalstrength. Thus, the fatigue strength of the underlying zirconium metalis improved, thereby increasing the potential life of the prosthesis. Incontrast, oxidation of titanium alloys tends to form multiple oxides oftitanium, which are less well attached to the metal substrate, andimportantly, stabilizes the lower strength α-phase which significantlyreduces the metal's fatigue strength.

The air, oxygen, steam, and water oxidation processes are described innow-expired U.S. Pat. No. 2,987,352 to Watson, the teachings of whichare incorporated by reference as though fully set forth. The airoxidation process provides a firmly adherent black, blue-black, or bluelayer of essentially zirconium oxide (ZrO₂) of mainly monocliniccrystalline form, depending upon specific conditions of oxygen and watervapor levels during the process. If the oxidation process is continuedto excess, the coating will whiten and tend to separate from the metalsubstrate. An in situ oxidation step may be conducted in either oxygen,air, steam, hot water, salt baths or fluidized beds. For convenience,the substrate may be placed in a furnace having an oxygen-containingatmosphere (such as air) and typically heated at 700°-1100° F. up toabout 6 hours. However, other combinations of temperature and time arepossible. When higher temperatures are employed, the oxidation timeshould be reduced to avoid the formation of the a less-adherent oxide.

It is preferred that a blue-black zirconium oxide layer ranging inthickness from less than one micron up to about 6 microns should beformed, although thicker coatings ranging from about 1 to about 20microns are also useful. For example, furnace air oxidation at 1000° F.for 3 hours will form an oxide coating on Zircadyne 705 about 3-4microns thick. Longer oxidation times and higher oxidation temperatureswill increase this thickness, but may compromise coating integrity ifthickness exceeds about 20 microns. For example, one hour at 1300° F.will form an oxide coating about 14 microns in thickness, while 21 hoursat 1000° F. will form an oxide coating thickness of about 7 to about 9microns. Of course, because only a thin oxide is necessary on thesurface, only very small dimensional changes, typically less than 10microns over the thickness of the prosthesis, will result. In general,thinner coatings (up to about 6 microns) have better attachmentstrength, and more favorable residual surface stresses.

One of the salt-bath methods, also considered in situ methods, that maybe used to apply the zirconium oxide coatings to the metal alloyprosthesis, is the method of U.S. Pat. No. 4,671,824 to Haygarth, theteachings of which are incorporated by reference as though fully setforth. The salt-bath method provides a similar, slightly more abrasionresistant blue to black zirconium oxide coating. The method requires thepresence of an oxidation compound capable of oxidizing zirconium in amolten salt bath. The molten salts include chlorides, nitrates,cyanides, and the like. The oxidation compound, sodium carbonate, ispresent in small quantities, up to about 5 wt. %. The addition of sodiumcarbonate lowers the melting point of the salt. As in air oxidation, therate of oxidation is proportional to the temperature of the molten saltbath and the '824 patent prefers the range 550°-800° C. (1022°-1470° C).However, the lower oxygen levels in the bath produce thinner coatingsthan for furnace air oxidation at the same time and temperature. A saltbath treatment at 1290° F. for 4 hours produces an oxide coatingthickness of roughly 7 microns. Residual contaminants in the salt bathmay be inadvertently left on the treated implant surface and produceadverse clinical results. While some of these may be removed bypolishing and washing, it is nonetheless preferred to use the gas (air)oxidation/nitridation processes which provides less possibility ofcontamination by other elements.

Whether air oxidation in a furnace, in a fluidized bed, or salt bathoxidation is used, the zirconium oxide coatings are quite similar inhardness. For example, if the surface of a wrought Zircadyne 705 (Zr,2-3 wt. % Nb) substrate is oxidized, the hardness of the surface shows adramatic increase over the 200 Knoop hardness of the original metalsurface. The surface hardens of the blue-black zirconium oxide surfacefollowing oxidation by either the salt bath or air oxidation process isapproximately 1700-2000 Knoop hardness.

In situ air or oxygen oxidation is the preferred method for producingthe invention oxide coatings because it minimizes the potential forsurface contamination, and allows oxygen diffusion into the metalsubstrate thereby allowing the formation of a tightly adherent oxidecoating while also strengthening the zirconium or zirconium alloy metalsubstrate.

While the above discussion has dealt mainly with blue to black zirconiumoxide coatings, zirconium nitride (yellow-orange) coatings are alsoeffective in reducing wear on opposing surfaces and preventing corrosionof the underlying substrate by body fluids.

Even though air contains about four times as much nitrogen as oxygen,when zirconium or zirconium alloy is heated in air as described above,the oxide coating is formed in thermodynamic preference to the nitridecoating. This is because the thermodynamic equilibrium favors oxidationover nitridation under these conditions. Thus, to form an in situnitride coating the equilibrium must be forced into favoring the nitridereaction. This is readily achieved by elimination of oxygen and using anitrogen or ammonia atmosphere instead of air or oxygen when a gaseousenvironment (analogous to "air oxidation") is used.

In order to form an in situ zirconium nitride coating of about 5 micronsin thickness, the zirconium or zirconium alloy substrate should beheated to about 800° C. for about one hour in a nitrogen atmosphere.Thus, apart from the removal of oxygen (or the appropriate reduction inoxygen partial pressure), or increasing the temperature, conditions forforming the zirconium nitride coating do not differ significantly fromthose needed to form the blue to black zirconium oxide coating. Anyneeded adjustment would be readily apparent to one of ordinary skill inthe art.

When a salt bath method is used to produce an in situ nitride coating,then the oxygen-donor salts should be replaced with nitrogen-donorsalts, such as, for instance, cyanide salts. Upon such substitution, anitride coating may be obtained under similar conditions to those neededfor obtaining an oxide coating. Such modifications as are necessary maybe readily determined by those of ordinary skill in the art.

Alternatively, the zirconium oxide or nitride may be deposited onto thezirconium or zirconium alloy surface via other techniques than the insitu gaseous and salt bath methods described above. These methodsencompass, for example, standard physical or chemical vapor depositionmethods, including those using an ion-assisted deposition method.Techniques for producing such an environment are known in the art.

As in the case of the zirconium oxide coatings, the nitride coatings areuseful even at thicknesses as low as about 0.1 micron. However,thicknesses from about 1 to about 20 microns are preferred and the rangeabout 3 to about 6 microns is most preferred.

If desirable in the particular application, the zirconium oxide ornitride coated article may be further coated by silver doping orboronation to improve wear-resistance. Additionally, amorphousdiamond-like carbon, or other hard, biocompatible coatings may also beapplied to either the base low modulus metal or to the oxidized ornitrided surface layer. When deposited over the hard oxide or nitridesurface layer, amorphous diamond-like carbon and other types of hardoverlay coatings will have improved attachment strength due to a closerhardness match than that between such coatings and relatively softermetal surfaces.

Although the invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art may, uponreading this disclosure, appreciate changes and modifications which maybe made and which do not depart from the scope and spirit of theinvention as described above and claimed below.

I claim:
 1. A woven vascular graft for replacing an artery, vein orblood vessel in a living body, said woven vascular graft comprising:(a)a cylindrical substrate of a woven low elastic modulus metalliccomposition with a bore therethrough, said substrate having surfaces andsized to replace an artery, vein or blood vessel in a living body; and(b) a corrosion-resistant, biocompatible, hemocompatible, durable,stable coating selected from the group consisting of essentiallyzirconium oxides, ranging in color from blue to black, and essentiallyzirconium nitrides, ranging in color from yellow to orange; said coatingdisposed on said surfaces of the substrate.
 2. The woven vascular graftof claim 1, wherein the coating is from about 0.1 to about 20 micronsthick.
 3. The woven vascular graft of claim 1, wherein the substratecomprises a metal selected from the group consisting of zirconium andzirconium-containing alloys.
 4. The woven vascular graft of claim 3,wherein said substrate further includes a sub-surface zone containingdiffused oxygen.
 5. The woven vascular graft of claim 3 or claim 4,wherein the coating includes diffusion-bonded blue to black zirconiumoxides.
 6. The woven vascular graft of claim 5, wherein the coating isfrom about 0.1 to about 20 microns thick.
 7. The woven vascular graft ofclaim 1, further comprising a second coating selected from the groupconsisting of antibiotics and anticoagulants, wherein said secondcoating is disposed on said corrosion-resistant, biocompatible,hemocompatible, durable, stable coating.
 8. The woven vascular graft ofclaim 1 further comprising a silver-doped overlay coating over thecorrosion-resistant, biocompatible, hemocompatible, durable, stablecoating.
 9. The woven vascular graft of claim 1, further comprisingoverlay coatings over the coating, said overlay coatings selected fromthe group consisting of amorphous diamond-like carbon, cubic zirconia,and white tetragonal zirconia.
 10. The woven vascular graft of claim 1further includes a lubricous boronated overlay coating over thecorrosion-resistant, biocompatible, hemocompatible, durable, stablecoating.